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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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September 18, 2012

Going After the Big Cyclic Ones

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Posted by Derek

I wrote last year about macrocyclic compounds and their potential as drugs. Now BioCentury has a review of the companies working in this area, and there are more of them than I thought. Ensemble and Aileron are two that come to mind (if you count "stapled peptides" as macrocycles, and I think they should). But there are also Bicycle, Encycle, Lanthio, Oncodesign, Pepscan, PeptiDream, Polyphor, Protagonist, and Transzyme. These companies have a lot of different approaches. Many of them (but not all) are using cyclic peptides, but there are different ways of linking these, different sorts of amino acids you can use in them, and so on. And the non-peptidic approaches have an even wider variety. So I've no doubt that there's room in this area for all these companies - but I also have no doubt that not all these approaches are going to work equally well. And we're just barely getting to the outer fringes of sorting that out:

While much of the excitement over macrocycles is due to their potential to disrupt intracellular protein-protein interactions, every currently disclosed lead program in the space targets an extracellular protein. This reality reflects the challenge of developing a potent and cell-penetrant macrocyclic compound.

Tranzyme and Polyphor are the only companies with macrocyclic compounds in the clinic. Polyphor’s lead compound is POL6326, a conformationally constrained peptide that antagonizes CXC chemokine receptor 4 (CXCR4; NPY3R). It is in Phase II testing to treat multiple myeloma (MM) using autologous transplantation of hematopoietic stem cells.

Tranzyme’s lead compound is TZP-102, an orally administered ghrelin receptor agonist in Phase IIb testing to treat diabetic gastroparesis.

Two weeks ago, Aileron announced it hopes to start clinical development of its lead internally developed program in 2013. The compound, ALRN-5281, targets the growth hormone-releasing hormone (GHRH) receptor.

Early days, then. It's understandable that the first attempts in this area will come via extracellular-acting, iv-administered agents - those are the lowest bars to clear for a new technology. But if this area is going to live up to its potential, it'll have to go much further along than that. We're going to have to learn a lot more about cellular permeability, which is a very large side effect (a "positive externality", as the economists say) of pushing the frontiers back like this: you figure these things out because you have to.

Comments (11) + TrackBacks (0) | Category: Drug Development | Pharmacokinetics


1. ronathan richardson on September 18, 2012 8:51 AM writes...

Not sure if the link was in there somewhere, but here it is:

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2. JB on September 18, 2012 9:05 AM writes...

Broad too, although the library is not exclusively macrocycles- a range of ring sizes from 4 to 18, non-peptide-
PubMed IDs 22252910, 21875084, 21526820
One of the 14-member macrocycles is a malaria lead (PMID 22328964) so is likely getting into cells.
Also just announced a deal with AZ for screening against microbes.

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3. Nick Terrett on September 18, 2012 11:35 AM writes...

As CSO of one of the companies cited in the article (Ensemble Therapeutics), I should comment on cell penetration. We’ve been in the game of macrocycles for several years now and have now found many macrocycles that get into cells and are active against multiple intracellular targets. Our IL17 program, although an extracellular target, has generated compounds with oral bioavailability and efficacy in disease models.

So while there’s much still to be done in this space, our experience is that cellular penetration either as a prerequisite for oral bioavailability or as a necessity for hitting intracellular targets is fully attainable with macrocycles.

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4. Anonymous on September 18, 2012 3:27 PM writes...

Depends how you classify "macrocycle" I suppose. One could include two additional orally administered "macrocycles" that are currently under clinical development, both originating from S*Bio (Singapore). The first is SB-1513 (pacritinib), a JAK2/FLT3 inhibitor being developed to treat myeloproliferative disease. Pacritinib was acquired by "Cell Therapeutics" (Seattle, WA) earlier this year. The second is SB-1317 (TG02), also a JAK2/FLT3 inhibitor being developed to treat hematological disorders (licensed to Tragara Pharma, San Diego).

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5. AW on September 18, 2012 4:41 PM writes...

Just to let everybody know, an ACS medicinal chemistry symposium is being organized on exactly this topic for the fall meeting in Indianapolis 2013. Hope to see ya'll there.

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6. Anon on September 18, 2012 7:24 PM writes...

"Other naturally derived cyclic peptides include the antibiotics erythromycin and vancomycin, and the immunosuppressant tacrolimus."

Uhhh..Ahem...not exactly. I will give you vanco as a non-ribosomal peptidic product but erythro and FK-506 as macrocyclic peptides? 15 yards, loss of down.

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7. okemist on September 19, 2012 9:41 AM writes...

I know of a modified cyclosporin in the clinic as an oral anti-viral, but it has been over a year and I am not sure how far it has gotten.

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8. Anon on September 19, 2012 9:59 AM writes...

Any molecule that has the ability to adopt conformations that can hide its polarity has significantly higher chances of passively crossing membranes including, macrocycles. We should already start thinking about correcting for PSA and molecular polarity parameters for molecules that can adopt such conformations. More on this in our upcoming publication.

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9. As2O3 on September 21, 2012 9:33 PM writes...

Melanotan II would presumaby qualify as a macrocycle? That's already being injected by millions, as are a bunch of other unlicenced "research" peptides...

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10. Mfernflower on August 29, 2015 10:40 PM writes...

There are ton of anti-hep-c nightmarish macrocyclic drugs that seem to have appeared overnight:

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11. imgur on August 30, 2015 4:29 PM writes...

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